rs587778777

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_Very_Strong

The NM_000784.4(CYP27A1):c.1184+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,614,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001193887: Functional assessments of this variant are available in the literature (PMID:9392430)." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CYP27A1
NM_000784.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24

Conservation

PhyloP100: 9.81

Publications

20 publications found

Variant links:

Genes affected

CYP27A1 (HGNC:2605): (cytochrome P450 family 27 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This mitochondrial protein oxidizes cholesterol intermediates as part of the bile synthesis pathway. Since the conversion of cholesterol to bile acids is the major route for removing cholesterol from the body, this protein is important for overall cholesterol homeostasis. Mutations in this gene cause cerebrotendinous xanthomatosis, a rare autosomal recessive lipid storage disease. [provided by RefSeq, Jul 2008]

CYP27A1 Gene-Disease associations (from GenCC):

cerebrotendinous xanthomatosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

CYP27A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001193887: Functional assessments of this variant are available in the literature (PMID: 9392430).; SCV001205319: Studies have shown that disruption of this splice site results in skipping of 89 nucleotides of exon 6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 9392430).; SCV002072869: Experimental evidence shows that this variant activates a cryptic donor splice site and leads to skipping of 89 base pairs of exon 6, introduces a new reading frame and creates a premature stop codon that does not three essential amino acids (Lys354, Lys358, and Arg362) that are important for the ferredoxin-binding domain (Rashvand et al. 2021).; SCV002548099: The variant allele was found at a frequency of 0.00016 in 251280 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CYP27A1 causing Cerebrotendinous Xanthomatosis (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.1184+1G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Cerebrotendinous Xanthomatosis (example, Garuti_1996, Gianneschi_2013). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. no; SCV005397483: "A functiol study testing R splicing confirmed that this variant results in exon 7 skipping and generates a premature termition codon (PMID: 9392430)."; SCV000322121: Canonical splice site variant and published functional studies demonstrate that this variant leads to the production of three abnormal transcripts, and almost undetectable levels of mRNA in patient fibroblasts (Garuti et al., 1997); PMID: 10775536, 25525159, 11181744, 26643207, 20402754, 28894950, 29260356, 32793533, 33659184, 34066437, 33400472, 31589614, 33083013, 33520900, 9392430; SCV004852527: Experimental studies show this alteration results in abnormal splicing and introduces a frameshift (Garuti, 1997).

PP5

Variant 2-218814188-G-A is Pathogenic according to our data. Variant chr2-218814188-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 65833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000784.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP27A1	NM_000784.4	MANE Select	c.1184+1G>A		splice_donor intron	N/A	NP_000775.1	Q02318

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CYP27A1	ENST00000258415.9	TSL:1 MANE Select	c.1184+1G>A	splice_donor intron	N/A	ENSP00000258415.4	Q02318
CYP27A1	ENST00000901552.1		c.1184+1G>A	splice_donor intron	N/A	ENSP00000571611.1
CYP27A1	ENST00000901553.1		c.1202+1G>A	splice_donor intron	N/A	ENSP00000571612.1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000159

AC:

AN:

251280

AF XY:

0.000214

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000132

AC:

193

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000869

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000998

AC:

111

AN:

1112002

Other (OTH)

AF:

0.0000828

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000414

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cholestanol storage disease (14)

not provided (8)

Cardiovascular phenotype (1)

CYP27A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

PhyloP100

9.8

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over